Send to:

Choose Destination
See comment in PubMed Commons below
Mol Cancer Ther. 2012 Feb;11(2):416-26. doi: 10.1158/1535-7163.MCT-11-0559. Epub 2011 Dec 21.

Sorafenib sensitizes (-)-gossypol-induced growth suppression in androgen-independent prostate cancer cells via Mcl-1 inhibition and Bak activation.

Author information

  • 1Department of Biochemistry and Molecular Biology, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, PR China.


The natural BH3-mimetic (-)-gossypol shows promising efficacy in ongoing phase II/III clinical trials for human prostate cancer. Here, we show for the first time, that treatment with (-)-gossypol and multikinase inhibitor sorafenib synergistically suppresses the growth of androgen-independent prostate cancer cells (AI-PC) in vitro and in vivo. Our data suggest that sorafenib attenuates (-)-gossypol-induced Mcl-1 upregulation in AI-PCs. In this way, it serves as a potent chemosensitizer to affect cell death. Interestingly, (-)-gossypol and sorafenib induce cell death via two distinct pathways among different AI-PCs; DU145 cells via apoptosis and PC-3 via autophagy. The appointed death pathway may depend on the level of proapoptotic protein Bak, although the level of antiapoptotic protein Bcl-2 plays some role in it. DU145 cells with high Bak level prefer apoptosis induction, whereas PC-3 cells with low Bak prefer the induction of autophagy. Furthermore, inhibiting nondominant death pathways, that is, autophagy in DU145 and apoptosis in PC-3, enhances cell killing by (-)-gossypol/sorafenib combination therapy. Ultimately, our data expose a new action for sorafenib as an enhancer of (-)-gossypol-induced cell growth suppression and reveal a novel cell death mode by Bak activation manners in AI-PCs. These new insights may facilitate the rational design of clinical trials by selecting patients most likely to benefit from the Bcl-2-targeted molecular therapy.

[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Write to the Help Desk